A tissue adhesive means an adhesive used for biological tissues such as blood vessels, skin, and the like (hereunder, referred to as tissue), in an operation such as cardiovascular surgery. With use of this adhesive, it is possible to prevent blood leaking and such risks so as to improve the safety of the operation.
At present, there are three major types of tissue adhesives as follows.
The first adhesive is a cyanoacrylate based tissue adhesive, such as DERMABOND as a commercial product. This adhesive has a problem in that the biocompatibility is low, although the adhesive strength is high.
The second adhesive is a biopolymer-aldehyde based tissue adhesive, such as Gelatin Resolcinol Formaldehyde (GRF glue as a commercial product. This adhesive also has a problem in that the biocompatibility is low, although the adhesive strength is high.
The third adhesive is a fibrin based tissue adhesive, such as Bolheal as a commercial product. This adhesive has an opposite problem in that the adhesive strength is low, although the biocompatibility is high.
In this way, it has been so far a problem of this technology that there is no tissue adhesive satisfying both excellent properties of the adhesive strength and the biocompatibility.
In recent years, regarding the fibrin based tissue adhesive, it has been elucidated that a tissue adhesive comprising human serum albumin (hereunder, referred to as HSA) and a cross-linking reagent has high adhesive strength (Non-Patent Document 1).
HSA is a serum protein made from blood preparations. It is a globular protein having a diameter of about 10 nm with a molecular weight of 69,000. Moreover, this is a negatively charged acidic protein. In addition, disuccinimidyl tartarate (hereunder, referred to as DST) has been used as the cross-linking reagent.
However, since any product using a blood preparation is classified as a medicinal product, considerable efforts are required for the approval and clearance. Moreover, once it is approved as a medicinal product, the usage record has to be kept continually for 20 years after the approval. This requires considerable efforts, which is a problem.
For this reason, it has been considered to use gelatin as a non-blood preparation instead of HSA. For example, Patent Document 1 has disclosed a medical material prepared by crosslinking gelatin with succinimidized poly-L-glutamic acid. Moreover, Patent Document 2 relating to a tissue adhesive film has disclosed a tissue adhesive film made from gelatin or collagen. However, they have a problem in that the adhesive strength is not enough.
In addition, Patent Document 3 relating to a tissue adhesive formulation has disclosed a tissue adhesive formulation which comprises a mixture of a synthetic and/or cross-linkable material in a particulate form and a particulate material. However, this tissue adhesive formulation also has a problem in that the adhesive strength is not enough.
Furthermore, papers relating to gelatin in which an alkyl group has been introduced on the side chain, have been reported (Non-patent documents 2 and 3).
However, solving the above-mentioned problems has yet to be achieved.